Neddylation inhibition prevents acetaminophen-induced liver damage by enhancing the anabolic cardiolipin pathway.

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Autores de IDIVAL

  • Paula Iruzubieta Coz

    Autor

  • Javier Crespo García

    Autor

Autores ajenos al IDIVAL

  • Gil-Pitarch C
  • Serrano-Maciá M
  • Simon J
  • Mosca L
  • Conter C
  • Rejano-Gordillo CM
  • Zapata-Pavas LE
  • Peña-Sanfélix P
  • Azkargorta M
  • Rodríguez-Agudo R
  • Lachiondo-Ortega S
  • Mercado-Gómez M
  • Delgado TC
  • Porcelli M
  • Aurrekoetxea I
  • Sutherland JD
  • Barrio R
  • Xirodimas D
  • Aspichueta P
  • Elortza F
  • Martínez-Cruz LA
  • Nogueiras R
  • Masson S
  • McCain MV
  • Reeves HL
  • Andrade RJ
  • Lucena MI
  • Mayor U
  • Goikoetxea-Usandizaga N
  • González-Recio I
  • Martínez-Chantar ML

Unidades

Abstract

Drug-induced liver injury (DILI) is a significant cause of acute liver failure (ALF) and liver transplantation in the Western world. Acetaminophen (APAP) overdose is a main contributor of DILI, leading to hepatocyte cell death through necrosis. Here, we identified that neddylation, an essential post-translational modification involved in the mitochondria function, was upregulated in liver biopsies from patients with APAP-induced liver injury (AILI) and in mice treated with an APAP overdose. MLN4924, an inhibitor of the neuronal precursor cell-expressed developmentally downregulated protein 8 (NEDD8)-activating enzyme (NAE-1), ameliorated necrosis and boosted liver regeneration in AILI. To understand how neddylation interferes in AILI, whole-body biotinylated NEDD8 ((bio)NEDD8) and ubiquitin ((bio)UB) transgenic mice were investigated under APAP overdose with and without MLN4924. The cytidine diphosphate diacylglycerol (CDP-DAG) synthase TAM41, responsible for producing cardiolipin essential for mitochondrial activity, was found modulated under AILI and restored its levels by inhibiting neddylation. Understanding this ubiquitin-like crosstalk in AILI is essential for developing promising targeted inhibitors for DILI treatment.

Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

Datos de la publicación

ISSN/ISSNe:
2666-3791, 2666-3791

Cell Reports Medicine  CELL PRESS

Tipo:
Article
Páginas:
101653-101653
PubMed:
39019009
Enlace a otro recurso:
www.sciencedirect.com

Citas Recibidas en Web of Science: 4

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Keywords

  • APAP; DILI; NEDD8; mitochondria; necrosis

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